Neurotransmitter-gated ion channels adopt different gating modes to fine-tune signaling at central synapses. At glutamatergic synapses, high and low activity of AMPA receptors (AMPARs) is observed when pore-forming subunits coassemble with or without auxiliary subunits, respectively. Whether a common structural pathway accounts for these different gating modes is unclear. Here, we identify two structural motifs that determine the time course of AMPAR channel activation. A network of electrostatic interactions at the apex of the AMPAR ligand-binding domain (LBD) is essential for gating by pore-forming subunits, whereas a conserved motif on the lower, D2 lobe of the LBD prolongs channel activity when auxiliary subunits are present. Accordingly, channel activity is almost entirely abolished by elimination of the electrostatic network but restored via auxiliary protein interactions at the D2 lobe. In summary, we propose that activation of native AMPAR complexes is coordinated by distinct structural pathways, favored by the association/dissociation of auxiliary subunits.
This letter describes a multi-dimensional SAR campaign based on a potent, efficacious and selective GIRK1/2 activator (∼10-fold versus GIRK1/4 and inactive on nonGIRK 1-containing GIRKs, GIRK 2 or GIRK2/3). Further chemical optimization through an iterative parallel synthesis effort identified multiple ‘molecular switches’ that modulated the mode of pharmacology from activator to inhibitor, as well as engendering varying selectivity profiles for GIRK1/2 and GIRK1/4. Importantly, these compounds were all inactive on nonGIRK1 containing GIRK channels. However, SAR was challenging as subtle structural modifications had large effects on both mode of pharmacology and GIRK1/2 and GIRK1/4 channel selectivity.
A high-performance ultrasonic system for the simultaneous transmission of data and power through solid metal barriers
- IEEE transactions on ultrasonics, ferroelectrics, and frequency control
- Published almost 6 years ago
This paper presents a system capable of simultaneous high-power and high-data-rate transmission through solid metal barriers using ultrasound. By coaxially aligning a pair of piezoelectric transducers on opposite sides of a metal wall and acoustically coupling them to the barrier, an acoustic- electric transmission channel is formed which prevents the need for physical penetration. Independent data and power channels are utilized, but they are only separated by 25.4 mm to reduce the system¿s form factor. Commercial off-the-shelf components and evaluation boards are used to create realtime prototype hardware and the full system is capable of transmitting data at 17.37 Mbps and delivering 50 W of power through a 63.5-mm thick steel wall. A synchronous multi-carrier communication scheme (OFDM) is used to achieve a very high spectral efficiency and to ensure that there is only minor interference between the power and data channels. Also presented is a discussion of potential enhancements that could be made to greatly improve the power and data-rate capabilities of the system. This system could have a tremendous impact on improving safety and preserving structural integrity in many military applications (submarines, surface ships, unmanned undersea vehicles, armored vehicles, planes, etc.) as well as in a wide range of commercial, industrial, and nuclear systems.
- IEEE transactions on image processing : a publication of the IEEE Signal Processing Society
- Published about 4 years ago
Most common cameras use a CCD sensor device measuring a single color per pixel. The other two color values of each pixel must be interpolated from the neighboring pixels in the so-called demosaicking process. State-of-the-art demosaicking algorithms take advantage of inter-channel correlation locally selecting the best interpolation direction. These methods give impressive results except when local geometry cannot be inferred from neighboring pixels or channel correlation is low. In these cases, they create interpolation artifacts. We introduce a new algorithm involving non-local image self-similarity in order to reduce interpolation artifacts when local geometry is ambiguous. The proposed algorithm introduces a clear and intuitive manner of balancing how much channel-correlation must be taken advantage of. Comparison shows that the proposed algorithm gives state-of-the-art methods in several image bases.
The activation mode of the mechanosensitive ion channel, MscL, by lysophosphatidylcholine differs from tension-induced gating
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Published over 4 years ago
One of the best-studied mechanosensitive channels is the mechanosensitive channel of large conductance (MscL). MscL senses tension in the membrane evoked by an osmotic down shock and directly couples it to large conformational changes leading to the opening of the channel. Spectroscopic techniques offer unique possibilities to monitor these conformational changes if it were possible to generate tension in the lipid bilayer, the native environment of MscL, during the measurements. To this end, asymmetric insertion of l-α-lysophosphatidylcholine (LPC) into the lipid bilayer has been effective; however, how LPC activates MscL is not fully understood. Here, the effects of LPC on tension-sensitive mutants of a bacterial MscL and on MscL homologs with different tension sensitivities are reported, leading to the conclusion that the mode of action of LPC is different from that of applied tension. Our results imply that LPC shifts the free energy of gating by interfering with MscL-membrane coupling. Furthermore, we demonstrate that the fine-tuned addition of LPC can be used for controlled activation of MscL in spectroscopic studies.-Mukherjee, N., Jose, M. D., Birkner, J. P., Walko, M., Ingólfsson, H. I., Dimitrova, A., Arnarez, C., Marrink, S. J., Koçer, A. The activation mode of the mechanosensitive ion channel, MscL, by lysophosphatidylcholine differs from tension-induced gating.
The photodissociation of jet cooled benzyl radicals, C7H7, at 248 nm has been studied using photofragment translational spectroscopy. Two dissociation channels were observed, H + C7H6 and CH3 + C6H4. The translational energy distribution determined for each channel suggests that both dissociation mechanisms occur via internal conversion to the ground state followed by intramolecular vibrational redistribution and dissociation. The branching ratio between these two channels has been measured to be CH3 + C6H4 : H + C7H6 = 0.011 ± 0.004. The dominance of the H + C7H6 channel is corroborated by the branching ratio calculated using Rice-Ramsperger-Kassel-Marcus theory.
- Proceedings of the National Academy of Sciences of the United States of America
- Published 12 months ago
The form and function of river deltas is intricately linked to the evolving structure of their channel networks, which controls how effectively deltas are nourished with sediments and nutrients. Understanding the coevolution of deltaic channels and their flux organization is crucial for guiding maintenance strategies of these highly stressed systems from a range of anthropogenic activities. To date, however, a unified theory explaining how deltas self-organize to distribute water and sediment up to the shoreline remains elusive. Here, we provide evidence for an optimality principle underlying the self-organized partition of fluxes in delta channel networks. By introducing a suitable nonlocal entropy rate ([Formula: see text]) and by analyzing field and simulated deltas, we suggest that delta networks achieve configurations that maximize the diversity of water and sediment flux delivery to the shoreline. We thus suggest that prograding deltas attain dynamically accessible optima of flux distributions on their channel network topologies, thus effectively decoupling evolutionary time scales of geomorphology and hydrology. When interpreted in terms of delta resilience, high nER configurations reflect an increased ability to withstand perturbations. However, the distributive mechanism responsible for both diversifying flux delivery to the shoreline and dampening possible perturbations might lead to catastrophic events when those perturbations exceed certain intensity thresholds.
CaV1.3 channels regulate excitability in many neurons. As is the case for all voltage-gated channels, it is widely assumed that individual CaV1.3 channels behave independently with respect to voltage-activation, open probability, and facilitation. Here, we report the results of super-resolution imaging, optogenetic, and electrophysiological measurements that refute this long-held view. We found that the short channel isoform (CaV1.3S), but not the long (CaV1.3L), associates in functional clusters of two or more channels that open cooperatively, facilitating Ca(2+) influx. CaV1.3S channels are coupled via a C-terminus-to-C-terminus interaction that requires binding of the incoming Ca(2+) to calmodulin (CaM) and subsequent binding of CaM to the pre-IQ domain of the channels. Physically-coupled channels facilitate Ca(2+) currents as a consequence of their higher open probabilities, leading to increased firing rates in rat hippocampal neurons. We propose that cooperative gating of CaV1.3S channels represents a mechanism for the regulation of Ca(2+) signaling and electrical activity.
We report a novel method for fabrication of three-dimensional (3D) biocompatible micro-fluidic flow chambers in polydimethylsiloxane (PDMS) by 3D-printing water-soluble polyvinyl alcohol (PVA) filaments as master scaffolds. The scaffolds are first embedded in the PDMS and later residue-free dissolved in water leaving an inscription of the scaffolds in the hardened PDMS. We demonstrate the strength of our method using a regular, cheap 3D printer, and evaluate the inscription process and the channels micro-fluidic properties using image analysis and digital holographic microscopy. Furthermore, we provide a protocol that allows for direct printing on coverslips and we show that flow chambers with a channel cross section down to 40 μm × 300 μm can be realized within 60 min. These flow channels are perfectly transparent, biocompatible and can be used for microscopic applications without further treatment. Our proposed protocols facilitate an easy, fast and adaptable production of micro-fluidic channel designs that are cost-effective, do not require specialized training and can be used for a variety of cell and bacterial assays. To help readers reproduce our micro-fluidic devices, we provide: full preparation protocols, 3D-printing CAD files for channel scaffolds and our custom-made molding device, 3D printer build-plate leveling instructions, and G-code.
When conventional high-volume, low-pressure cuffs of endotracheal tubes (ETTs) are inflated, channel formation due to folds in the cuff wall can occur. These channels facilitate microaspiration of subglottic secretions, which is the main pathogenic mechanism leading to intubation-related pneumonia. Ultrathin polyurethane (PU)-cuffed ETTs are developed to minimize channel formation in the cuff wall and therefore the risk of microaspiration and respiratory infections.